Tracing oncogene-driven remodelling of the intestinal stem cell niche

Min Kyu Yum, Seungmin Han, Juergen Fink, Szu-Hsien Sam Wu, Catherine Dabrowska, Teodora Trendafilova, Roxana Mustata, Lemonia Chatzeli, Roberta Azzarelli, Irina Pshenichnaya, Eunmin Lee, Frances England, Jong Kyoung Kim, Daniel E. Stange, Anna Philpott, Joo-Hyeon Lee, Bon-Kyoung Koo () and Benjamin D. Simons ()
Additional contact information
Min Kyu Yum: University of Cambridge
Seungmin Han: University of Cambridge
Juergen Fink: University of Cambridge
Szu-Hsien Sam Wu: Vienna Biocenter (VBC)
Catherine Dabrowska: University of Cambridge
Teodora Trendafilova: University of Cambridge
Roxana Mustata: University of Cambridge
Lemonia Chatzeli: University of Cambridge
Roberta Azzarelli: University of Cambridge
Irina Pshenichnaya: University of Cambridge
Eunmin Lee: DGIST
Frances England: University of Cambridge
Jong Kyoung Kim: DGIST
Daniel E. Stange: University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden
Anna Philpott: University of Cambridge
Joo-Hyeon Lee: University of Cambridge
Bon-Kyoung Koo: University of Cambridge
Benjamin D. Simons: University of Cambridge

Nature, 2021, vol. 594, issue 7863, 442-447

Abstract: Abstract Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence1–3. Although mosaic analyses in Drosophila have advanced our understanding of such interactions4,5, it has been difficult to engineer parallel approaches in vertebrates. Here we present an oncogene-associated, multicolour reporter mouse model—the Red2Onco system—that allows differential tracing of mutant and wild-type cells in the same tissue. By applying this system to the small intestine, we show that oncogene-expressing mutant crypts alter the cellular organization of neighbouring wild-type crypts, thereby driving accelerated clonal drift. Crypts that express oncogenic KRAS or PI3K secrete BMP ligands that suppress local stem cell activity, while changes in PDGFRloCD81+ stromal cells induced by crypts with oncogenic PI3K alter the WNT signalling environment. Together, these results show how oncogene-driven paracrine remodelling creates a niche environment that is detrimental to the maintenance of wild-type tissue, promoting field transformation dominated by oncogenic clones.

Date: 2021
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DOI: 10.1038/s41586-021-03605-0

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